P1041: LEUKOCYTOSIS SELECTS A SUBGROUP OF LOW-RISK PV PATIENTS IN WHOM PHLEBOTOMY-ALONE MAY BE INSUFFICIENT
Authors: Alessandra Carobbio, Alessandro Vannucchi, Valerio De Stefano, Arianna Ghirardi, Greta Carioli, Arianna Masciulli, Elena Rossi, Fabio Ciceri, Massimiliano Bonifacio, Alessandra Iurlo, Francesca Palandri, Giulia Benevolo, Fabrizio Pane, Alessandra Ricco, Giuseppe Carli, Marianna Caramella, Davide Rapezzi, Caterina Musolino, Sergio Siragusa, Elisa Rumi, Andrea Patriarca, Nicola Cascavilla, Barbara Mora, Emma Cacciola, Carmela Mannarelli, Giuseppe Gaetano Loscocco, Paola Guglielmelli, Francesca Gesullo, Silvia Betti, Francesca Lunghi, Luigi Scaffidi, Cristina Bucelli, Nicola Vianelli, Marta Bellini, Maria Chiara Finazzi, Gianni Tognoni, Alessandro Rambaldi, Tiziano Barbui
Journal: HemaSphere (2023)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: The Low-PV randomized clinical trial provided evidence that ropeginterferon alpha-2b (ropeg) was superior to phlebotomy alone to maintain HCT on target (≤45%) in conventionally defined low-risk patients with polycythemia vera (PV), irrespective of platelet and leukocyte (WBC) counts. Each enrolled patient (n=127) was phlebotomized before starting treatment until the target hematocrit ≤45% was achieved. After 12 months of therapy, the primary endpoint was met in 81% (ropeg) and 51% (standard arm) respectively. Responders continued the assigned treatment for additional 12 months while non-responders were crossed over to the alternative treatment. Aims: To identify the minimum number and timing of phlebotomies qualifying non-responders and investigate the significance of leukocytosis in phlebotomized patients during the 24-months study. Methods: Phlebotomy-only responders vs. non-responders were compared; responders were stratified by WBC values at randomization and through 12 and 24 months. Results: (i)Compared to responders (n=32, 51%), non-responders (n=31, 49 %) were more frequently males (74% vs. 50%, p=0.048) harboring higher but not statistically different JAK2V617F allele burden (42% vs. 27%, p=0.59). After 12 months, in addition to higher HCT values (46.2% vs. 44.1%, p=0.005), non-responders exhibited higher WBC counts (15.8 x109/L vs. 9.8 x109/L, p=0.018) and number of phlebotomies per-patient (5 vs. 2, p=0.007). The greater demand of phlebotomies in non-responders was evident as early as the 6th month (3 vs. 1 phlebotomies per-patient, p=0.001), so that the prediction of treatment response given by the number of phlebotomies per-patient at 6 and 12 months was superimposable by ROC analysis (AUC: 0.767 vs. 0.764, respectively). Of note, in 6 of these patients, progressive symptomatic thrombocytosis, TIA (n=1) and splenic thrombosis (n=1) were registered. (ii)Responders to phlebotomy-only had a low phlebotomy requirement (median 2 per-patient/year) in both the first and second semesters and were stratified according to WBC counts at randomization (< or ≥ 10 x109/L): 14 (44%) presented and maintained up to 24 months a median WBC of 8x109/L vs. 18 (56%) in whom the WBC median was 13x109/L. As compared with the responders with normal WBC counts, responders with leukocytosis also had higher platelet counts (600 x109/L vs 700 x109/L, p=0.033), a trend to elevated values of LDH in 11/18 (61%) vs 4/14 (29%) (p= 0.087) and to a higher JAK2V617F variant allele frequency (VAF) (20% vs. 60%, p=0.07, Figure). Summary/Conclusion: (i)The minimum number of phlebotomies per-patient qualifying non-responders was 3 per semester; these patients can be identified in the first 6 months and may be switched to ropeg treatment earlier than 12 months. (ii)A subgroup of responders (56%), albeit with a low need for phlebotomies, presented a profile indicating a more pronounced myeloproliferation, sustained by leukocytosis, higher JAK2V617F VAF and elevated LDH, that is considered a quantitative measure of cell turnover and tumor burden. (iii)Responders with normal WBC, normal LDH and lower JAK2V617F VAF were overall 14/63 (22%) of low-risks randomized to phlebotomy-only; these patients benefited from phlebotomy-only, in spite of moderately elevated platelet number. These findings support the recent ELN guidelines suggesting to consider interferon-alpha in the subgroup of young low-risk PV patients with persistent leukocytosis.Figure. JAK2V617F VAF in responder patients stratified by median WBC 13x109/L vs 8x109/L at randomization and after 12 and 24 months. Keywords: Therapy, Polycythemia vera, Leukocytes, Myeloproliferative disorder